Microdosing in Translational Medicine: Pros and Cons

SUMMARY

Microdosing in Translational Medicine: Pros and Cons evaluates this innovative approach to investigating candidate molecules.

The CREAM trial and other studies have largely validated the concept of human microdosing (HMD) as a reliable screen for basing go/no go decisions to Phase I. CHA predicts human microdosing (HMD) will first be used by smaller drug developers with limited resources, finding broader acceptance by the industry as a routine "litmus test" by 2012. Orest Hurko, AVP of Translational Research at Wyeth, expects 75% of biopharma companies to implement it over the next 5 years.

Microdosing in Translational Medicine: Pros and Cons provides a balanced evaluation of the pros and cons of HMD, including:

• What the CREAM trial and other HMD studies say about the linearity of PK results.
• Comparative assessment of EMEA and FDA guidelines governing HMD - which offers the more hospitable pathway?
• Use of HMD in synergy with in silico and other predictive technologies.
• Assessment of current detection technologies and emerging improvements.
• Use of PET in HMD to study ligand displacement.
• Which sector will adopt HMD first --- big pharma or biotechs?
• Applications of HMD using oral, IV, and other routes of administration.
• Examination of cost-benefit, risk management, regulatory and ethical aspects of HMD.

Microdosing in Translational Medicine: Pros and Cons is based upon:

• Roundtable interviews with CEOs of the leading CROs specializing in HMD.
• A survey of the views, actions and planned activities of R&D managers at pharma and biotech companies with responsibility for selecting candidates for Phase I.
• Forecast of the market for HMD services and timelines to adoption by pharma and biotech companies.

About the Author

Hermann A.M. Mucke, Ph.D. spent 17 years in academia and industry before he founded H.M. Pharma Consultancy (www.hmpharmacon.com) in 2000 to become an independent pharmaceutical consultant, analyst and science author. His last industry position was Vice President R&D in a European pharmceutical company which he helped to take public on the Frankfurt Stock Exchange in 1999. Since then, Dr. Mucke, who holds a Ph.D. in biochemistry from the University of Vienna (Austria) became a consultant and advisory board member for several European and U.S. pharmaceutical companies, and a regular reviewer of drugs and patents for Thomson Current Drugs and Ashley Publications. He has served as an outside expert author for CHA since 2004. Dr. Mucke is based in Vienna and can be reached at h.mucke@hmpharmacon.com , or by fax at +43 1 494 9989.

TABLE OF CONTENTS

Chapter 1. Introduction: The Quest for Early Human Data

• 1.1 A Quicker and Safer Way to Develop New Drugs is Needed
• 1.2 The Basic Dilemma: Extrapolating from Animals to Humans
• 1.3 Better Software Will Help, But Solutions for Judging Effects on Humans are Needed Now
• 1.4 The Concept of Microdosing

Chapter 2. Microdosing and Clinical Pharmacology

• 2.1 The Benefit of Early Human Pharmacodynamic Information
• 2.2 Expected Relations between Microdoses and Clinically Effective Doses
• 2.3 Microdosing Known Compounds to Assess Investigational Drug Effects
• 2.4 Bioanalytical Support: Constraints and Perspectives
  • Accelerator Mass Spectrometry
  • Tandem Liquid Chromatography/Mass Spectroscopy
  • Positron-Emission Tomography
• 2.5 Using Microdosing-Type Analytical Methods in Safety Pharmacology

Chapter 3. Microdosing Studies as a Strategic Tool

• 3.1 Microdosing as a Tool to Weigh Drug Development Options
• 3.2 A Fruitful Marriage with in silico Optimization Techniques and "-omics"
• 3.3 Option for Studies in Unconventional Populations

Chapter 4. Microdosing as a Regulatory Challenge and Opportunity

• 4.1 The EMEA Position Paper on Microdosing
• 4.2 The FDA Exploratory IND Guideline
• 4.3 Other Regulatory Guidelines for Studies Using Radioactive Drugs
• 4.4 Benefits in Costs, Time, and Logistics
• 4.5 The Ethical Aspect: Reducing the Burden on Volunteers and the Use of Animals

Chapter 5. Practical Experience and Planning-Stage Projects with Microdosing

• 5.1 Proof of Concept through In Vitro and Animal Studies
• 5.2 Collaborative Industry and Public/Private Efforts
  • The Consortium for Resourcing and Evaluating AMS Microdosing
  • Azidothymidin Study by Radiant Research and Vitalea Sciences
  • The EU Microdose AMS Partnership Programme (EUMAPP)
• 5.3 Pharmaceutical Companies as Sponsors of Microdosing Studies
  • GlaxoSmithKline
  • Servier
  • Speedel Pharmaceuticals
  • Tripep
  • Neurocrine Biosciences
  • Industry Opinions on the Acceptance of Microdosing

Chapter 6. Expert Roundtable Commentaries

• Dr. Ali Arjomand, President and COO, Accium Biosciences
• Dr. Stephen Dueker, President, Vitalea Science
• Dr. Jon Ruckle, Medical Director, Early Phase Research, Radiant Research
• Dr. Lloyd Stevens, Business Support Manager, Pharmaceutical Profiles
• Prof. Dr. Colin Garner, CEO, Xceleron

• Question 1: Do you see possibilities for modifying current microdosing protocals to make them more predictive?
• Question 2: Do you see additional potential in evaluating other parameters relevant to drug development, such as drug interactions?
• Question 3: How do you estimate the potential of isotopes other than 14C?
• Question 4: How do you see the relationship between AMS and LC/MS/MS developing?
• Question 5: What role do you see for imaging technologies, expecially PET, in microdosing studies?
• Question 6: Could human microdosing be accepted to such an extent that it becomes a routine screening tool for drug leads in a streamlined clinical development process?
• Question 7: Could you comment on the potential feedback loops between human microdosing studies, the various "-omics," and in silico methods?
• Question 8: Do you see opportunities for microdosing in formal preclinical study programs?
• Question 9: With EMEA and FDA guidelines in place, how do you think the scenery will develop geographically during the next few years?
• Question 10: What are your optimistic and pessimistic estimates for the dollar volume of the microdosing market by 2010 and 2015?
• Question 11: What share of this market do you estimate your company will capture by 2010 and 2015?

Chapter 7. Conclusion: Cambridge Healthtech Associates' Scenario for Microdosing in Drug Development

• 7.1 Today's Outlook Depends on Where You Are in the Drug Development Process
• 7.2 Along the Way: Getting Over Nonscientific and Noneconomic Factors
• 7.3 An Exciting New Tool

Appendix A.

• Companies Offering Microdosing Services

Appendix B.

• Cambridge Healthtech Associates - Microdosing Survey - April 2006-04-24

References

Company Index with Web Addresses